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| Item Type: | Preprint |
|---|---|
| Title: | Coordinated IFN-γ/TNF axis drives selective loss of activated enteric glia in inflammatory bowel diseases |
| Creators Name: | Bubeck, M., Penkert, K.A., Limberger, H., González Acera, M., Plattner, C., Ziegler, S., Muppirala, A.N., Forster, P., Jakob, M., Gamez-Belmonte, R., Erkert, L., Kulkarni, S., Günther, C., Atreya, R., Kühl, A.A., Hegazy, A., Hildner, K., Trajanoski, Z., Siegmund, B., Neurath, M.F., Rao, M., Progatzky, F., Lie, D.C., Becker, C., Romagnani, C., Ludwig, L.S., Klose, C.S.N. and Patankar, J.V. |
| Abstract: | BACKGROUND: Enteric glial cells (EGC) play a crucial role in maintaining gut homeostasis, but their dysregulation in inflammatory bowel diseases (IBD) remains poorly understood. Emerging preclinical data suggests activated EGC have beneficial roles in controlling gut pathophysiology. OBJECTIVE: Understanding EGC activation and adaptation during experimental and clinical IBD. DESIGN: We provide the first highly integrated approach to identify EGC activation signature in IBD. Profiling 390 samples from IBD patients via bulk and single-nucleus (sn) transcriptomics and replicate the findings on publicly available bulk and single-cell (sc) datasets from 1160 patients and 19,000 single EGC. Preclinical modelling of Th1/Th17 inflammation, reporter-assisted EGC sorting, analysis of regulated cell death, and Casp8 ablation in EGC was performed. RESULTS: We identified novel IBD type and sampling associated EGC activation signature. Specific EGC activation markers were shared in biopsies and resection specimens, and were divergent between Crohns disease and Ulcerative colitis. Preclinical modelling of intestinal inflammation identified combinatorial TNF and IFN-γ-driven activation of EGC, associated with elevated necroptosis, and negatively impacting gut motility. Genetic-reporter-enabled sorting and downstream analyses confirmed TNF and IFN-γ-driven EGC necroptosis, potentiated by Casp8 deficiency. Furthermore, snRNA-Seq from IBD patient samples confirmed elevated cell death signature in activated but not in rare neuroglia progenitor-like cluster. CONCLUSION: Our findings identify IBD type-associated activated EGC markers involved in immune and epithelial homeoastasis. We uncover necroptosis of activated EGCs as a constituent of intestinal inflammation. Advancing our understanding of activated EGC survival is pivotal in elucidating their complex roles in maintaining gut immune-epithelial homeostasis. |
| Keywords: | Inflammatory Bowel Disease, Activated Enteric Glial Cells, Single Nucleus MRNA Sequencing, Necroptosis, Gut Motility, Animals, Mice |
| Source: | bioRxiv |
| ISSN: | 2692-8205 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.04.03.646820 |
| Date: | 3 April 2025 |
| Additional Information: | Leif S. Ludwig and Ashley D. Sanders are members of the TRR241 IBDome Consortium. |
| Official Publication: | https://doi.org/10.1101/2025.04.03.646820 |
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